This invention relates to a new process for the preparation of dopamine agonists such as Cabergoline, to some novel intermediates used in this process and to their preparation.
N-(Ergoline-8xcex2-carbonyl) ureas of formula [1]
wherein R1 represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a phenyl group or a dimethylamino alkyl group xe2x80x94(CH2)nNMe2 in which n is an integer, R2 represents any of the groups which R1 may represent, or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl residue, R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, R4 represents a hydrogen or a halogen atom or a methylthio or phenylthio group and R5 represents a hydrogen atom or a methyl group; have shown potent dopamine agonist properties and have been useful as anti-Parkinson drugs and as prolactin inhibitors (U.S. Pat. No. 5,382,669 and Eur. J. Med. Chem., 1989, v. 24, 421).
One of the most potent prolactin inhibitor of this class is 1-(6-alkylergoline-8xcex2-carbonyl)-1-[3-(dimethylamino)propyl]-3-ethylurea (international non-proprietary name Cabergoline) [1a] (Eur. J. Med. Chem., 1989, v.24, 421) which was firstly prepared by reaction of 6-alkylergoline-8xcex2-carboxylic acid [7] with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (U.S. Pat. No. 4,526,892) (Scheme 1). 
In this case both regioisomers [1a] and [8] were obtained and the yield of the isolated Cabergoline [1a] is low as a consequence of isolation difficulties.
Another method for Cabergoline preparation (Eur. J. Med. Chem., 1989, v, 24, 421 and BP 2,13,603) was based on the direct reaction of N-[3-(dimethylamino)propyl]-6-alkylergoline-8xcex2-carboxamide [2a] with ethyl isocyanate (Scheme 2): 
However, this approach required large amounts of ethyl isocyanate (up to 40 eq.) and reflux in toluene for several days. The use of large quantities of toxic isocyanate under drastic reaction conditions represented the major limitation for the large-scale preparation of Cabergoline by this route.
The method proposed in U.S. Pat. No. 5,382,669 and Syn. Lett., 1995, 605 is based is on copper salts catalyzed reaction of ethyl isocyanate with carboxamide [2a] using phosphorous ligands. Drawbacks of this approach are the use of heavy metal ions or, the final step of the synthesis and decreasing chemoselectivity with increasing conversion of this reaction.
All the previously disclosed methods for the preparation of Cabergoline present serious drawbacks for producing material suitable for use as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise a new synthetic method, which avoids use of heavy metal salts, and which cleanly produces the desired Cabergoline [1a] under mild reaction conditions, avoiding tedious and expensive purification steps.
The present invention provides a commercially acceptable process for producing N-(ergoline-8xcex2-carbonyl)ureas of formula [I]: 
including their stereoisomers as well as acid addition salts thereof,
wherein R1 is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and (dimethylamino alkyl group xe2x80x94(CH2)nNMe2 in which n is an integer,
R2 is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group xe2x80x94(CH2)nNMe2 in which a is an integer, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl ,
R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and
R4 is selected from hydrogen halogen, methylthio and phenylthio group;
which process comprises silylating an ergoline-8-carboxamide of formula [2], 
including stereoisomers as well as metal or ammonium salts or acid addition salts thereof,
wherein R1, R2, R3 and R4 are as defined above,
reacting the obtained product with isocyanate of the formula [5]:
R1xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83[5]
Followed by Desilylation
This novel approach was used for the preparation of the known antiprolactinic and anti-Parkinson agent Cabergoline [1a] and related compounds. 
Other features and advantages will be apparent from the specification and claims.
The present invention describes a novel process for the preparation of N-(ergoline-8xcex2-carbonyl)urea compounds of formula [I]. Particularly, the present invention utilizes the silylation of of ergoline-8xcex2-carboxamide [2] in order to selectively activate it""s amide group in the subsequent reaction with isocyanate.
This novel approach has the following advantages:
Silylated ergoline-8xcex2-carboxamides react with isocyanates to give, after desilylation of intermediates, the desired N-(ergoline-8xcex2-carbonyl)ureas [I] with high yield and purity.
Reagents used for silylation and desilylation are not toxic, commercially available and inexpensive.
Although any silylating agents, suitable for silylating amides, can be used for silylating ergoline-8xcex2-carboxamide [2], a compound of formula [3] is preferably used for this purpose to give intermediate N-silylamide of the formula [4], tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof; intermediate [4] reacts with isocyanate of formula [5 ]: 
wherein R6, R7 and R8 may be the same or different and are selected from the group consisting of alkyl having from 1 to 6 carbon atoms, aryl and aralkyl radicals;
Y is selected from the group consisting of chloro, bromo, iodo, (haloalkyl)-sulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, (trialkylsilyloxy)sulfonyloxy, imidazolyl, N-acyl-N-alkylamino, N-acyl-N-(trialkylsily) amino, (trialkylsilyl)-amino, N,N-dialkylamino, isopropenyloxy, 1-alkoxy-1-alkenyloxy and trichloroacetoxy radicals;
and R1, R2, R3 and R4 are as defined above, to give O-silylated N-[ergoline-8xcex2-carbonyl]urea represented by formula [6]: 
including, tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof,
wherein R1, R2, R3, R4, R6, R7 and R8 are as defined above; following desilylation of the above compound(s) to obtain the desired N-(ergoline-8xcex2-carbonyl)urea [I], which can be converted into acid addition salts thereof.
The silylating agent may be used in a 0.5 to 10 fold molar amount, preferably from 0.9 to 5 fold molar amount, relative to the amount of the ergoline-8xcex2-carboxamide [2]. Preferably, silylating agents are selected from trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate, trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl chloride, bromide or iodide, trimethylsilyl trichloroacetate and trifluoroacetate, 1-(trimethylsilyl)imidazol, 1-(trimethylsilyl)-1,2,4-triazole, 1-(trimethylsilyl)-1H-benzotriazole, 1-(trimethylsilyl)-2-pyrrolidinone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, methyl trimethylsilyl dimethylketene acetal, bis(trimethylsilyl)sulfate, N,O-bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide.
The silylation reaction may be cared out from xe2x88x9250xc2x0 C. to the reflux temperature of the reaction mixture. Preferably, the silylation is carried out from 0xc2x0 to 50xc2x0 C.
Organic or inorganic acids or salts may accelerate the silylation. Examples of such acids include mineral acids such as sulfuric acid or hydrogen halide. Examples of salts include metal halides, tertiary ammonium halides, ammonium halides, ammonium sulfate, pyridine or it""s derivatives hydrohalides. However, preferably, organic or inorganic bases accelerate the silylation reaction. Examples of organic bases are tertiary amines, sterically hindered secondary amines, pyridine or there derivatives, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof. Examples of tertiary amines include 1-ethylpiperidine, 1-butylpyrrolidine, diisopropylethylamine, triethylamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane or mixture thereof. Examples of sterically hindered secondary amines are diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethylpiperidine or mixture thereof. Examples of pyridine derivatives are 4-dimethylaminopyridine (DMAP), 4-(4-methylpiperidino)pyridine and 4-pyrrolidinopyridine or mixture thereof.
The solvent for the silylation reaction may be any suitable aprotic organic solvent provided it does not inhibit the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides such as dichloromethane and chloroform; ether solvents such as ether, isopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide or 1-methylpyrrolidinone (NMP).
The resultant silylated product may be used in the following step after isolation from the reaction mass, or may be subjected to the subsequent step without isolation.
After silylation, the resultant product is reacted with a compound of formula [5], which may be used in a 1 to 10 fold molar amount, preferably 2 to 5 fold molar aunt relative to the amount of the ergoline-8xcex2-carboxamide [2]. The reaction may be carried out at temperature from xe2x88x9250xc2x0 C. to reflux temperature of the reaction mixture. Preferably, the reaction is carried out at 0-50xc2x0 C. without a isolating silylated ergoline-8xcex2-carboxamide from the reaction mass.
The reaction of silylated ergoline-8xcex2-carboxamide with isocyanate may be carried out without solvent but preferably, the reaction is carried out in any organic aprotic solvent which does not inhibit the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides such as dichloromethane and chloroform; ether solvents such as ether isopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, N,N-dimethylformamide (DMF),N,N-dimethylacetamide or 1-methylpyrrolidinone (NMP).
Optionally, the reaction of silylated ergoline8xcex2-carboxamide with isocyanate may be accelerated by transition metal(s) salt(s) and/or coordination compound(s) or fluoride-ions. Examples of the said transition metals include copper or zinc. Preferably, the said transition metal(s) salt(s) are copper and/or zinc halides. Preferably the said ligands in the coordination compound(s) with transition metal(s) contain phosphorous, nitrogen and/or oxygen atoms. Examples of the ligands include triarylphosphines, pyridine or it""s derivatives, tertiary amines, nitriles, amides and ether-type compounds.
The desilylation can be carried out by, for example, using fluoride salts optionally in the presence of phase transfer catalysts. Examples of the said fluoride salt include tetraalkylammonium fluoride, benzyltrialkylammonium fluoride and alkali metal fluoride. Examples of the said phase transfer catalysts include tetraalkylammonium salts, benzyltrialkylammonium salts and crown ethers.
Cabergoline [1a] may be prepared from amide [2a] according to Scheme 3: 
The invention will be further described in more detail with the following non-limiting examples,